Iontophoresis and conductivity analysis circuit

ABSTRACT

An iontophoresis inducing circuit includes means to limit to a safe value and to control a generated direct current for connection to iontophoresis electrides on a patient in order to produce sweat. A sweat sample is collected and analyzed to detect for cystic fibrosis. A sweat analysis circuit includes solid state switching for passing current of continuously alternating polarity through the sweat sample, and nonlinear means for converting the current into a direct reading of milliequivalents of sodium chloride per liter.

United States Patent Ninke Feb. 26, 1974 ION'IOPIIORESIS ANDCONDUCTIVITY ANALYSIS CIRCUIT Filed:

Inventors: Donald A. Ninke, Austin, Teic;

James F. LaIIay, St. Louis, Mo.

Assignee: Sherwood Medical Industries, Inc.,

St. Louis, Mo. I

July 26, 1971 Appl.'No.: 166,284

Related US. Application Data Division of Ser.

abandoned.

No. 880,807, Nov. 28, 1969,

US. Cl. 324/30 R, 128/21 R Int. Cl. Gln 27/02, A61b /00 Field of Search.324/30 R, 30 B, 29, 62, 57 P1,

References Cited UNITED STATES PATENTS Odorici 324/1 Si1verman.,.. 324/B X, Schneider.... 324/30 Broach 128/21 R 3,079,556 2/1963 Connelly eta1 324/131 3,302,102 1/1967 Lace.... 324/30 B 3,399,037 8/1968 Eckfeldt324/30 B FOREIGN PATENTS OR APPLICATICNS 860,681 2/1961 Great Britain324/132 OTHER PUBLICATIONS Silicon Zener Diode and Rectifier Handbookpub. by Motorola-l96l pp. 112-113.

Primary ExaminerAlfred E. Smith Assistant ExaminerRolf Hille [57]ABSTRACT An iontophoresis inducing circuit includes means to limit to asafe value and to control a generated direct current for connection toiontophoresis electrides on a patient in order to produce sweat. A sweatsample is collected and analyzed to detect for cystic fibrosis. A

a sweat analysis circuit includes solid state switching for passingcurrent of continuously alternating polarity through the sweat sample,and nonlinear means for converting the current into a direct reading ofmilliequivalents of sodium chloride per liter.

10 Claims, 1 Drawing Figure NOCI MlLLlEQUlVALENTS PER LITER PATENTEDFE826 I974 m rzwrhad mmk] mum m on on on 0 selected level.

This application is a divisional application of copending applicationSer. No. 880,807, filed Nov. 28, 1969, now abandoned.

This invention relates to a circuit for effectuating iontophoresis andanalyzing the products obtained therefrom.

lontophoresis is a medical technique for introducing drugs throughintact skin. In the detection of cystic fibrosis in children, it isknown that the great majority of children suffering with cystic fibrosishave an abnormally high concentration of sodium chloride in their sweat.An effective means of detecting such disease is to collect sweatproduced by pilocarpine iontophoresis, and analyze the sweat forchloride concentration by using various methods including conductivityof the sweat sample. I

Localized sweating may be induced by using electrodes filled withiontophoresis inducing solutions. The electrodes, after being strappedto a patients arm, are connected to a source of DC voltage. Due todifferences in individual patients, and other. factors includingplacement of the electrodes onthe patient, the amount, of direct currentpassed through the' electrodes may vary widely, and in somecircumstances may reach unsafe levels. Prior iontophoresis circuitshave-depended upon a technician continually monitoring a meter in, orderto insure that the current does not-exceed'a pre- The present inventionprovides in part an improved iontophoresis circuit which eliminates theproblems of prior circuits by. insuring that the direct current passed.to the iontophoresis electrodes cannot exceed' a preselected maximumvalue. The desired value of current can be selected once by thetechnician, and the circuit automatically compensates for differencesbetween various patients.

After the iontophoresis electrodes have been energized for a short timeperiod, the source of DC therefore is deactuated and the electrodes areremoved from the patients arm. Skin area into whichpilocarpine has beeninduced will now produce localized sweating, allowing the sweat to becollected in order to be analyzed.

Typical prior circuits for analyzing a sweat sample use a multivibratorto continuously energize and then deenergize a relay. The contacts ofthe relay, which.

switch at the frequency of. the multivibrator, connect different DCpolarities to a bridge circuit which includes the resistivity of thesweat sample. Additional relay contacts connect the bridge circuit to'aDC meter. The meter reading, which only indicates the conductivity ofthesweat sample, must be converted by the technician into milliequivalentsof sodium chloride per liter, by using a nonlinear graph.

Such prior circuits have many disadvantages. Electromechanical switchingby relays or the like cause the analyzer to require frequent servicing.The circuit itself is complex and expensive to build and maintain.Furthermore, the visual output is an oscillating value which isdifficult to read, and is not the final desired reading, but must beconverted by use of a chart, all of which increase the possibility oferror.

The present invention provides, in part, an improved analyzer circuitwith solid state components for-eliminating electromechanical switching.Furthermore, by use of a nonlinear and scale expanding circuit, theconductivity of the sweat sample is converted directly into a reading ofsodium chloride milliequivalents per liter, eliminating charts and othersources of error, and saving the time of the technician.

One object of this invention is the provision of an improved circuit foreffectuating iontophoresis and then analysis of sweat samples obtainedthereby.

One feature of this invention is the provision of an iontophoresiscircuit which includes a current limitor for preventing current toiontophoresis electrodes from exceeding a predetermined level, and whichincludes means for timing the duration of the current flow and forcontrolling the magnitude of current flow to the patient.

Another feature of this invention is the provision of a conductivityanalysis circuit which employs all solid state components to eliminateelectromechanical switching.

Yet another feature of this invention is the provision of a sweatanalysis circuit which has a direct, readout of milliequivalents ofsodium chloride per unit volume.

Further features and advantages ofthe invention will i While anillustrative embodiment of the invention is shown in the -drawing andwill be described in detail herein, the invention is susceptible ofembodiment in many different forms and it should be understood that thepresent disclosure is to be considered as an exemplification of theprinciples of the invention and is not intended to limit the inventionto the embodiment illustrated. Throughout the specification, values andtype designations will be given for certain of the components in orderto disclose a complete, operative embodiment of the invention. However,it should be understood that such values and type designations aremerely representative and are not critical unless specifically sostated. The scope of the invention will be pointed out in the appendedclaims.

Turning to the single FIGURE, a circuit is illustrated which includes asection 10 for effectuating iontophoresis, and a section 12 foranalyzing a sweat sample obtained after iontophoresis of a patient, withcertain elements of the circuit being used in common by both sections ofthe circuit. lontophoresis section 10 generates a direct current whichis supplied to a pair of output terminals 14 and 15. By means of plugs17 and 18, the direct current is supplied to a pair of iontophoresiselectrodes 20 and 21, illustrated on the arm of a patient.

lontophoresis electrodes 20 and 21 may be any conventional electrodesused for the purpose of inducing localized sweating. Typically, oneelectrode would be filled with a 0.5 percent solution of pilocarpinenitrate, and the other electrode with a 1 percent solution of sodiumnitrate. After being strapped to the patients arm, positive DC voltageavailable from output terminal 14 is connected to the electrodecontaining pilocarpine nitrate, and negative DC voltage available fromoutput terminal 15 is connected to the electrode connecting sodiumnitrate. By way of example, the electrodes may be of the form disclosedin the copending application of Richard A. Reeves, Ser. No. 880,767, nowU.S. Pat. No. 3,677,268 entitled iontophoresis Electrode, filed on evendate herewith, and assigned to the assignee of the present application.

After about 5 minutes of iontophoresis the circuit automatically stopsthe flow of current, and plugs 17 and 18 may be removed and theelectrodes 20 and 21 removed from the patients arm. When using theiontophoresis technique for the detection of cystic fibrosis, theforearm of the patient is washed with distilled water and wiped dryafter which a sweat collecting cup 25 is placed over the forearm wherethe electrode containing pilocarpine nitrate was located.

After about a 25 minute time period, the contents of the sweatcollecting cup 25 are measured to determine the concentration of sodiumchloride by analysis section 12, in order to detect for the presence ofcystic fibrosis in the patient. By way of example, the sweat collectingcup 25 may include a pair of electrodes for direct connection to a pairof input receptacle leads 27 for analysis section 12. Such a combinationcup and electrodes is shown in the copending application of James F.LaHay, Ser. No. 880,810, now U.S. Pat. No. 3,635,213 entitled Collectionand Measuring Electrode, filed on even date herewith, and assigned tothe assignee of the present application. If other types of collectionapparatus are used, it is necessary to transfer the sample into someholder of predetermined volume, which is adapted for connection toreceptacle leads 27, in order to allow a current to pass through thesweat sample. The circuit section 12 produces a reading on a meterindicator 30 which is directly calibrated in units of sodium chloridemilliequivalents per liter, or other unit volume.

Considering the circuit in detail, a source 33 of AC voltage suppliespower through a fuse 34 and singlepole, single-throw switch 35 to theprimary winding 37 of a step-down transformer 38. A neon lamp 40 iscoupled across primary winding 37 to indicate when switch 35 is closedto supply power to the circuit. A secondary winding 42 of transformer 38supplies AC voltage to both the iontophoresis section and the analysissection 12 of the circuit.

For powering iontophoresis section 10, secondary winding 42 is coupledto series connected diode 45 and 100 microfarad capacitor 46. Diode 45and capacitor 46 form a half wave rectifier. The resulting DC voltageavailable across capacitor 46 is coupled through a single-pole,single-throw switch 47 and a normally closed single-pole, single-throwrelay switch 48 from a timer 49 to a voltage divider consisting of a1,500 ohm resistor 52 in series with a 6,800 ohm resistor 53. Resistor52 is shunted by a 1,000 microfarad capacitor 55, for reasons to beexplained.

In order to automatically compensate for differences between patients, aconstant current source is provided in order to control the flow ofcurrent to terminals 14 and and maintain the flow at a selectable fixedcurrent value even though different patients are connected to theelectrodes and 21. The current source includes a semiconductor device asa PNP transistor 57, type 2N3638, having its emitter electrode 57ecoupled through a 6,000 ohm potentiometer 59 to the junction betweenswitch 48 and resistor 52. Potentiometer 59 includes a wiper shorted toone side of the variable resistor in order that the resistance value canbe continuously varied from zero to the maximum value, herein 6,000ohms. The base electrode 57b is directly coupled to the junction betweenvoltage divider resistors 52 and 53. The collector electrode 57c iscoupled through a 33 ohm resistor 61 and a 6,800 ohm resistor 62 tooutput terminal 14. Output terminal 15 is coupled to the junctionbetween capacitor 46 and resistor 53, which junction also serves as asource of reference potential or ground 64. Resistor 61 provides avoltage drop thereacross for monitoring the current to the electrodes 20and 21. This voltage drop is supplied to the left most illustratedterminals of a two position switch 66, the ganged wipers 67 and 68 ofwhich connect to the positive and negative input terminals,respectively, of meter 30, in the form of a DC voltmeter.

A scale 70 on meter 30 indicates the conductivity of the sweat samplesanalyzed by section 12, as will appear, and also may be used torelatively indicate the range of current which is flowing to effectuateiontophoresis. Potentiometer 59 is adjusted by the technician performingiontophoresis to select the current value that the constant currentsource thereafter maintains regardless of the impedance characteristicsof the patient. Resistor 62 insures that the iontophoresis current islimited to a safe value should the solid state current source fail.

in operation, the technician straps the electrodes 20 and 21 to thepatients arm and connects the plugs 17 and 18 to the'output terminals 14and 15. Thereafter, switch 47 is closed to supply DC power to theconstant current source, thereby generating current to effectuateiontophoresis. At the same time, the DC power is also supplied to timer49, which has a timing period equal to the desired time duration thatcurrent should flow to effectuate iontophoresis, such as 5 minutes.Capacitor 55 causes the iontophoresis current to increase gradually toreduce patient discomfort at initial energization of the electrodes 20and 21. This eliminates the need for the technician to perform thisfunction. After the lapse of the timing period, timer 49 energizes aninternal relay (not illustrated) to cause relay contact 48 to open,thereby terminating the iontophoresis current. Now, the technician mayremove the electrodes 20 and 21, open switch 47, and collect a sweatsample in cup 25. The opening of switch 47 disconnects power from timer49, causing contact 48 to return to its normally closed position. Thecircuit is now returned to a rest position and is ready to analyze thesweat sample just obtained.

Analyzer section 12 is powered by DC voltage which continuouslyalternates in polarity. The alternating polarity DC source includes a680 ohm resistor 72 in series with a back-to-back pair of unidirectionalsemiconductor voltage breakdown devices, as Zener diodes 74 and 75,connected in shunt across secondary winding 42 of transformer 38. EachZener diode may be a type lZM62. The back-to-back Zener diodes 74 and 75are shunted by a 1,000 ohm potentiometer 77 connected in series with aparalleled 470 ohm resistor 79 and a thermistor 80. Potentiometer 77 hasa wiper 82 for supplying current to the remainder of analyzer section Inoperation, the Zener diodes 74 and 75 square the alternating currentfrom secondary winding 42, and in effect form a source of essentiallyfixed magnitude DC voltage, which switches polarity at a rate equal tothe frequency of AC source 33. Thermistor 80 is chosen to have a curvewhich compensates for changes in ambient temperature which wouldotherwise affect the magnitude of square waves coupled to wiper 82.

Wiper 82 is connected to a solid state, full wave rectifier network 84consisting of four unidirectional conduction devices such as diodes 85,86, 87 and 88, connected to form a full wave bridge. Wiper 82 connectsto the junction between diodes 85 and 86. The corresponding junction onthe opposite side of the bridge,-

namely, between diodes 87 and 88, is coupled to one of the terminals 27of the sweat sample. The opposite of terminals 27 is connected to ground64, which forms the opposite side of the square wave voltage supply.

Since the sweat sample is in series with the square wave supply for fullwave bridge rectifier 84, the resistivity of the sweat sample directlyaffects the magnitude of current to the bridge circuit. The output ofthe bridge circuit, in the form of, full wave rectified DC I squarewaves, is available across a 3,400 ohm resistor 90 connected to thejunctions between diodes 85 and 88 and diodes 86 and 87. Therefore, themagnitude of direct currentthrough resistor 90 is directly proportionalto the conductivity of the sweat sample, which in turn indicates therelative concentration of sodium chloride for the given volume of sweatsample contained in cup 25.

As is well known, the curve ofsodium chloride millie quival ents perunit volume is not directly 'linearly'related to the resistivity of asweat sample. 'Prior analyzers have require'd a technician to read anonlinear graph in order to convert a current indication,- such asavailable from resistor 90, into an appropriate reading. In the present'circuit, this is automatically accomplished by a conversion networkinserted between re sistor 90 and voltmeter 30. When analyzer section 12is to be operative, switch '66 is thrown so that the right handillustrated contacts connect to wipers 67 and 68. In this position, oneside of resistor 90 is directly connected to the negative input ofvoltmeter30. The positive input to the voltmeter is connected through apair of series connected, nonlinear conducting elements having asemiconductor junction, such as diodes 92 and 93, to the opposite sideof resistor 90, which connects to ,the junction between diodes 85 and88. Diodes 9 2 and 93, such as type lN400l, are chosen to have nonlinearconducting curves which expand themeter scale Other equivalent uses forthe circuit will be apparent to those skilled in the art.

We claim:

1. A circuit for analyzing the concentration of sodium chloride in asample of sweat from a patient for detecting cystic fibrosis comprising:means for generating a current proportional to the conductivity of thesample; indicator means having a scale with indicia directly readable inmilliequivalents of sodium chloride per unit measure of volume of sweat;and circuit means coupled between said generating means and saidindicator means for supplying current to said indicator means inresponse to said proportional current, said circuit means includingnon-linear means connected to said indicator means to reduce thenon-linearity of said current supplied to said indicator means withrespect to the concentration of sodium chloride in the sample over acurrent range corresponding to the most clinically significant range fordetecting cystic fibrosis, said scale indicia being correlated with saidcurrent supplied to said indicator means to provide readings in saidclinically significant range.

2. The circuit of claim 1 wherein said nonlinear means comprise at leastone unidirectional conduction device having a semiconductor junction.

3. The circuit of claim 1 wherein said generating means includes asource of AC, solid state means coupled to said AC source causing acurrent which continuously alternates in polarity to flow in a firstcircuit path which includes said sample at a substantially constantvoltage value, said circuit means including solid state'means coupledbetween said first circuit path and 70 where the readings have the mostclinical significance, namely at mid-scale.

In operation, the current through resistor '90 produces a voltage dropwhich causes current to pass in a nonlinear manner through diodes 92 and93"to produce a reading on the scale 70. of voltmeter 30. The scale 70is marked with advancing indicia, directly in terms of milliequivalentssodium chloride per volume unit. Thus, upon connecting a sample of sweatto inputs 27, a direct reading in terms of the final desired quantity isobtained. The illustrated circuit also provides various peripheraladvantages concerning the use of solid state components and theregulated source of square wave voltage. These include elimination ofperiodic calibration and testing which would otherwise be required. Ofcourse, analysis section 12 may be used to measure the conductivity offluids other than sweat, and scale 70 may be calibrated in unitsappropriate to the particular conductivity readings of samples which areto be analyzed by the unit. For example, the scale 70 may be calibratedin terms of total electrolyte concentration.

said indicator means for converting the current of continuouslyalternating polarity into a direct current, and

said indicator means being responsive to direct current.

.4. The circuit of claim 3 wherein said solid state converting meansincludes full wave rectifying means for producing full wave rectifieddirect current from the current flowing in said first circuit path.

rent through 'said sample of sweat and full-wave rectified currentthrough said non-linear means and said indicator means.

7. A circuit for analyzing the concentration of sodium'chloride in asample of sweat from a patient for detecting cystic fibrosis comprisingcircuit means including voltage supply means, a pair of spaced electrodes coupled to said supply means for passing current through a sampleofsweat, and voltage dropping means coupled to said electrodes and saidsupply means for providing a voltage drop across the, voltage droppingmeans proportional to the conductivity of the sample of sweat, a meterindicator having a scale with indicia thereon for directly readingsodium chloride milliequivalents per unit volume of sweat, and meanscouvoltage drop to thereby reduce the non-linearity of said meterindicator-current with respect to the concentration of sodium chloridein the sample over a range of current values corresponding to the mostclinically significant range for detecting cystic fibrosis, said indiciabeing correlated with said meter indicator current and substantiallyequally spaced over said clinically significant range.

8. The circuit of claim 7 wherein said voltage supply means includes asource of alternating current for passing alternating current throughthe sample of sweat, said voltage dropping means comprises resistancemeans connected in series circuit relation with said electrodes and saidsupply means, and said non-linear wave rectified current through saidmeter.

1. A circuit for analyzing the concentration of sodium chloride in asample of sweat from a patient for detecting cystic fibrosis comprising:means for generating a current proportional to the conductivity of thesample; indicator means having a scale with indicia directly readable inmilliequivalents of sodium chloride per unit measure of volume of sweat;and circuit means coupled between said generating means and saidindicator means for supplying current to said indicator means inresponse to said proportional current, said circuit means includingnon-linear means connected to said indicator means to reduce thenonlinearity of said current supplied to said indicator means withrespect to the concentration of sodium chloride in the sample over acurrent range corresponding to the most clinically significant range fordetecting cystic fibrosis, said scale indicia being correlated with saidcurrent supplied to said indicator means to provide readings in saidclinically significant range.
 2. The circuit of claim 1 wherein saidnonlinear means comprise at least one unidirectional conduction devicehaving a semiconductor junction.
 3. The circuit of claim 1 wherein saidgenerating means includes a source of AC, solid state means coupled tosaid AC source causing a current which continuously alternates inpolarity to flow in a first circuit path which includes said sample at asubstantially constant voltage value, said circuit means including solidstate means coupled between said first circuit path and said indicatormeans for converting the current of continuously alternating polarityinto a direct current, and said indicator means being responsive todirect current.
 4. The circuit of claim 3 wherein said solid stateconverting means includes full wave rectifying means for producing fullwave rectified direct current from the current flowing in said firstcircuit path.
 5. The circuit of claim 1 wherein said scale indicia aresubstantially equally spaced over said range of milliequivalents, andsaid scale includes numbers directly reading in milliequivalents ofsodium chloride per unit measure of volume of sweat.
 6. The circuit ofclaim 5 wherein said current generating means include a source ofalternating current and a full-wave rectifier connected to passalternating current through said sample of sweat and full-wave rectifiedcurrent through said non-linear means and said indicator means.
 7. Acircuit for analyzing the concentration of sodium chloride in a sampleof sweat from a patient for detecting cystic fibrosis comprising circuitmeans including voltage supply means, a pair of spaced electrodescoupled to said supply means for passing current through a sample ofsweat, and voltage dropping means coupled to said electrodes and saidsupply means for providing a voltage drop across the voltage droppingmeans proportional to the conductivity of the sample of sweat, a meterindicator having a scale with indicia thereon for directly readingsodium chloride milliequivalents per unit volume of sweat, and meanscoupling said voltage dropping means to said meter indicator includingnon-linear means to supply current to said meter indicator which isnon-linear with respect to said voltage drop to thereby reduce thenon-linearity of said meter indicator current with respect to theconcentration of sodium chloride in the sample over a range of currentvalues corresponding to the most clinically significant range fordetecting cystic fibrosis, said indicia being correlated with said meterindicator current and substantially equally spaced over said clinicallysignificant range.
 8. The circuit of claim 7 wherein said voltage supplymeans includes a source of alternating current for passing alternatingcurrent through the sample of sweat, said voltage dropping meanscomprises resistance means connected in series circuit relation withsaid electrodes and said supply means, and said non-linear means isconnected in series with said meter in parallel circuit relation withsaid resistance means.
 9. The circuit of claim 8 wherein said circuitmeans further includes solid state rectifier means coupled between saidmeter and said electrodes whereby said meter current is rectified. 10.The circuit of claim 9 wherein said rectifier means is a full-waverectifier connected in series circuit relation with said electrodes topass alternating current from said supply means to said electrodes andpass full-wave rectified current through said meter.